1. Field of the Invention
This invention relates to synthetic chemical compounds which are tetrapeptides and exhibit inhibitory activity against enzymes such as aminopeptidases.
2. Description of the Prior Art
Several physiologically active peptides or N-acylated peptides have been found in the culture broths by some of the present inventors. These substances, e.g. leupeptin, antipain, chymostatin and pepstatin, inhibit trypsin, papain, chymotrypsin and pepsin, respectively, but all these inhibitors have their effects on proteases which act in endo-type reaction. For further disclosures of these see Enzyme Inhibitors of Microbial Origin, Hamao Umezawa, University of Tokyo Press (1972) in Chapter IV, Inhibitors of Proteolytic Enzymes (pages 15-52) as follows:
______________________________________ Peptides Page Number ______________________________________ Leupeptin 15 Antipain 29 Chymostatin 32 Pepstatin 34 ______________________________________
Bestatin, which has also been found in a microbial culture broth, inhibits an exo-type proteolytic enzyme, i.e. aminopeptidase B and leucine aminopeptidase, but it does not have any inhibitory effect on aminopeptidase A [U.S. Pat. No. 4,029,547].
Bestatin has the chemical name [(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl]-L-leucine and the following structure ##STR3## Other peptides were disclosed in U.S. Pat. No. 4,189,604 which claimed compounds having the formula ##STR4## wherein R.sup.1 is ##STR5## wherein R.sup.3 is hydrogen, chloro, methyl, nitro, hydroxy or amino and n is 0 or 1 and R.sup.2 is (lower)alkyl having 1 to 6 carbon atoms, hydroxy(lower)alkyl, alkylthioalkyl, carboxamide(lower)alkyl or carboxy(lower)alkyl provided that when R.sup.1 is benzyl and R.sup.2 is isobutyl the configuration of the compound is (2S,3R2'R), (2S,3S,2'S) or (2S,3S,2'R).
The present authors have discovered that Streptomyces sp. ME98-M3(FERM-P 3722) produces new tetrapeptide compounds of the formula (II) named amastatins which contain at the N-terminal a new .beta.-amino acid unknown in the literature and having the formula ##STR6## wherein R is a carboxymethyl or 2-carboxyethyl group, and found that these tetrapeptide compounds not only inhibit aminopeptidase A but also stimulate the antibody formation (U.S. Pat. No. 4,167,448; J. Antibiotics 31(6) 636-638, 1978). In the present specification, the said new .beta.-amino acid, 3-amino-2-hydroxy-5-methylhexanoic acid, is abbreviated AHMHA and its residue AHMHA-.